Abnormalities of the cellular components of the inflammatory response have been described in patients with diabetes mellitus. We and others have reported abnormal polymorphonuclear leukocyte (PMN) chemotaxis, adhesion, phagocytosis and bactericidal activity in patients with both adult and juvenile onset diabetes mellitus. Many of these functional activities are correctable by in vitro incubation with insulin, but the mechanism of this correction is unknown. Furthermore, there are almost no studies on the functional activities of macrophages or monocytes (MN's) from diabetic patients. The first objective of the proposed research will be to investigate monocyte function including chemotaxis, chemiluminescence, phagocytosis, and glucosamine incorporation in patients with juvenile and adult onset diabetes mellitus. An attempt will be made to correlate abnormal function with the stage of the disease, prescence of complications, degree of control and number of insulin receptors present on phagocytes. Correction of abnormal function with insulin will be attempted in vitro and in vivo. The second objective of the proposed research will be to determine the role of cyclic GMP and cyclic AMP in insulin's action to correct abnormal diabetic phagocyte function. Levels of these cyclic nucleotides will be measured in diabetic and control leukocytes using a new modification of the radioimmunoassay recently developed in our laboratory. Changes in the levels of phagocyte cAMP and cGMP in response to insulin and other pharmacologic agents will be monitored and correlated with insulin receptors and functional activity of the leukocytes. It is hoped that these studies will lead to a better understanding of the mechanism of action of insulin and to the development of regimens for the pharmacologic modification of abnormal diabetic phagocyte function. Since previous studies have indicated the similarities between insulin interaction with leukocytes and more prominent but less accessible target such as liver, muscle and fat cells, we hope the present work will have even wider application in understanding and treating the diabetic state.